Compounds

• US 20060058287A1
• Filed: 06/25/2003
• Published: 03/16/2006
• Est. Priority Date: 06/26/2002
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Gallagher, Timothy Francis, Axten, Jeffrey Michael, Miller, William Henry, Pendrak, Israil, Pearson, Neil David, Davies, David Thomas, Jones, Graham Elgin, Daines, Robert A
• Granted Patent: US 7,498,326 B2
• Time in Patent Office: Days
• US Class Current: 514/224.200
• CPC Class Codes: A61K 31/03 aromatic
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/54 having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.

Claims

1-16. -16. (canceled)

17. A compound of formula (I) or a pharmaceutically acceptable derivative thereof:

18. A compound according to claim 17 wherein R^A is optionally substituted isoquinolin-5-yl, quinolin-8-yl, thieno[3,2-b]pyridin-7-yl, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl, quinoxalin-5-yl, isoquinolin-8-yl, [1,6]-naphthyridin-4-yl, 1,2,3,4-tetrahydroquinoxalin-5-yl or 1,2-dihydroisoquinoline-8-yl.

19. A compound according to claim 17 wherein R¹ is H, methoxy, methyl, cyano or halogen and R^1a is H.

20. A compound according to claim 17 wherein R³ is hydrogen;

optionally substituted hydroxy;

optionally substituted amino;

halogen;

(C_1-4)alkoxycarbonyl;

CONH₂;

1-hydroxyalkyl;

CH₂CO₂H;

CH₂CONH₂;

—

CONHCH₂CONH₂;

1,2-dihydroxyalkyl;

CH₂CN;

2-oxo-oxazolidin-5-yl;

or 2-oxo-oxazolidin-5-yl(C_1-4alkyl).

21. A compound according to claim 17 wherein n is 0 and A and B are both CH₂, A is CHOH and B is CH₂ or A is NH and B is CO.

22. A compound according to claim 17 wherein -U- is —

CH₂—

.

23. A compound according to claim 17 wherein the heterocyclic ring (A) having 8-11 ring atoms including 2-4 heteroatoms of which at least one is N or NR¹³ in which Y² contains 2-3 heteroatoms, one of which is S and 1-2 are N, with one N bonded to X³ or the heterocyclic ring (A) has ring (a) aromatic selected from optionally substituted benzo and pyrido and ring (b) non aromatic and Y² has 3-5 atoms, including a heteroatom bonded to X⁵ selected from O, S or NR¹³, where R¹³ is other than hydrogen, and NHCO bonded via N to X³, or O bonded to X³.

24. A compound according to claim 17 wherein R⁵ is selected from:

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl

3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl

7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl

7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl

2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl.

25. A compound according to claim 17 selected from:

4-(2-{4-[(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylmethyl)-amino]-piperidin-1-yl}-ethyl)-quinoline-6-carbonitrile 6-({(3R,4S)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one

6-({(3S,4R)-3-Fluoro-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one

6-({(3R,4R)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one

6-({(3S,4S)-3-Hydroxy-1-[(R)-2-hydroxy-2-(2-methoxy-quinolin-8-yl)-ethyl]-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one

6-({(3R,4S)-1-[2-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-3-fluoro-piperidin-4-ylamino}-methyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one

6-{[(1-{(2R/S)-2-hydroxy-2-[3-(methyloxy)-5-quinoxalinyl]ethyl}-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

(1R/S)-2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-1-piperidinyl}-1-[3-(methyloxy)-5-quinoxalinyl]ethanol

{1-[2-(9-Chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-yl)-ethyl]-piperidin-4-yl}-(2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-amine 6-{[(1-(2-hydroxy-2-[2-(methyloxy)-8-quinolinyl]ethyl)-4-piperidinyl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

6-[({1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile (isomer E2)

4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile (isomer E2)

4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile (E1 isomer)

4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methyl]amino}-1-piperidinyl)ethyl]-6-quinolinecarbonitrile (E1 isomer)

or a pharmaceutically acceptable derivative thereof.

26. A method of treatment of bacterial infections in mammals, particularly in man, which method comprises the administration to a mammal in need of such treatment an effective amount of a compound according to claim 17.

27. A pharmaceutical composition comprising a compound according to claim 17, and a pharmaceutically acceptable carrier.

28. A process for preparing a compound of formula (I) according to claim 17, or a pharmaceutically acceptable derivative thereof, which process comprises reacting a compound of formula (IV) with a compound of formula (V):